Neuronal Substrates of Hemodynamic Signals in the Prefrontal Cortex PIs: Dr. John P. O'Doherty and Dr. Doris Tsao Institution: California Institute of Technology PROJECT SUMMARY fMRI is the dominant technique for probing human prefrontal cortex functions in cognition, learning and decision-making. This work is predicated on the assumption that fMRI activation relates in a principled manner to the underlying neuronal activity in a given area of prefrontal cortex. Yet, virtually nothing is known about how fMRI activations relate to the underlying neural computations within the prefrontal cortex. The absence of knowledge in this domain is in contrast to burgeoning work on the relationship between measured fMRI signals and neural responses in visual areas of the brain, illuminating for instance how neuronal responses in face responsive areas give rise to fMRI activations in the temporal lobes. Compared to visual cortical areas, neurons in prefrontal cortex have more sparse, heterogeneous, and functionally distributed response characteristics, thereby rendering the relationship between neuronal and fMRI responses more enigmatic. The overarching goal of this proposal is to elucidate the relationship between neuronal computations and fMRI responses in the same areas of the prefrontal cortex. To achieve this goal we will measure fMRI activity to identify the locus of activations in prefrontal cortex while separately recording neuronal activity using a multi- electrode recording system whose placement is guided by those fMRI activations. We will also probe the neurophysiological basis of functional connectivity typically found between regions of prefrontal cortex in human fMRI studies, by recording simultaneously from multiple regions identified as being functionally connected through our fMRI measurements. We will first address these questions in macaque monkeys, and then extend our findings directly to humans, scanning healthy human participants with fMRI, and making use of a rare opportunity to obtain both intracranial electrophysiological signals and fMRI scans from the prefrontal cortex in a group of human patients undergoing evaluation for surgical treatment of epilepsy. For behavioral tasks we will draw from the domain of value-based decision-making, because (a) such tasks involve multiple regions of prefrontal cortex in both monkey electrophysiology and human fMRI studies, (b) we can use virtually identical tasks with well constrained behavior in both species, and (c) most importantly, stark discrepancies exist between what is currently known about the response properties of single neurons in the prefrontal cortex of monkeys and activations measured with fMRI during decision-making tasks in humans, which are ripe for resolving with our proposed approach. By combining across these different techniques and methodologies in both humans and monkeys, we will be able to address the question of which aspects of underlying neuronal responses gives rise to the fMRI signal in prefrontal cortex. The work will provide an essential bridge between fMRI and finer-scaled electrophysiologically-based methods for studying high order cognitive function.